The Induction of Reactivity in Optic Nerve Astrocytes

视神经星形胶质细胞反应性的诱导

• 批准号: 8578401
• 负责人: RICHARD Harry MASLAND
• 金额: $ 40.96万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578401
• 关键词: Astrocytes; Axon; Belief; Biological; Brain; Cellular biology; Characteristics; Communication; Coupling; Distress; Down-Regulation; Environment; Eye; Fibrous Astrocyte; Future; Gene Expression; Gene Transfer; Genes; Glaucoma; Head; Hour; Human; Injury; Intermediate Filaments; Lead; Learning; Ligands; Light; Location; Mediating; Modeling; Molecular Profiling; Morphology; Mus; Mutation; Nature; Nerve; Nerve Crush; Optic Disk; Optic Nerve; Optics; Phase; Physiologic Intraocular Pressure; Research; Retinal Ganglion Cells; Signal Pathway; Signal Transduction; Spinal Cord; Staging; Stress; System; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Transgenic Mice; Up-Regulation; Viral Vector; axonal degeneration; cell injury; cell motility; functional group; ganglion cell; improved; overexpression; pressure; public health relevance; receptor; research study; response

Project Summary In both humans and mice, astrocytes form the immediate cellular environment of the ganglion cell axons in the optic nerve head. They occupy up to 50% of the total tissue volume at that location. When the axons of retinal ganglion cells are damaged, they become "reactive." In the proposed research we investigate the signaling between optic axons and the astrocyte that triggers this response. The first question is the nature and timing of the changes in gene expression that follow damage to the optic axons. Our preliminary results indicate that very different sets of glial genes are up or down regulated at different times following axonal injury. The experiments of Specific Aim 1 seek to confirm this finding, using an improved model of axonal damage. Specific Aim 2 uses the results of our existing and future expression profiling to identify candidates for the signaling systems that communicate from axons to astrocytes. The candidate signals will be overexpressed, using viral vectors, in retinal ganglion cells. The prediction is that overexpression of an actual signal will lead to the changes in astrocyte gene expression and morphology characteristic of astrocyte reactivity. Specific Aim 3 investigates the hypothesis that the initial response of the astrocytes to axonal damage is a protective one, i.e. that retinal ganglion cells threatened with injury send a distress signal to the ensheathing astrocytes, which then initiate a neuroprotective response. We will test this hypothesis by stressing the optic nerve in transgenic mice carrying mutations that compromise astrocyte communication and motility. The prediction is that the compromise of astrocyte function will worsen the damage to the axons resulting from this stress.

项目摘要 在人类和小鼠中，星形胶质细胞形成神经节细胞轴突的直接细胞环境 在视神经头。 它们占据该位置处的总组织体积的高达50%。 当 视网膜神经节细胞的轴突受损，它们变得“反应性”。“在拟议的研究中， 研究视神经轴突和星形胶质细胞之间触发这种反应的信号。 第一个问题是在细胞受损后基因表达变化的性质和时间。 视神经轴突我们的初步结果表明，非常不同的神经胶质基因组的上升或下降， 在轴突损伤后的不同时间调节。 具体目标1的实验试图证实 这一发现，使用一个改进的模型轴突损伤。 具体目标2使用我们现有的结果 和未来的表达谱分析，以确定候选人的信号系统， 轴突到星形胶质细胞 使用病毒载体，候选信号将在视网膜神经节中过表达， 细胞 预测实际信号的过度表达将导致星形胶质细胞基因的改变， 表达和星形胶质细胞反应性的形态学特征。 具体目标3研究了星形胶质细胞对轴突损伤的初始反应是 保护性的，即受到损伤威胁的视网膜神经节细胞向视网膜神经节细胞发出求救信号。 成鞘星形胶质细胞，然后启动神经保护反应。 我们将通过以下方式检验这一假设： 在携带损害星形胶质细胞突变的转基因小鼠中强调视神经 沟通和能动性。 据预测，星形胶质细胞功能的损害将使 这种压力对轴突造成的损伤。